This application claims priority to this Indian application numbers 2718/CHE/2012 filed on July 5, 2012 and 4039/CHE/2012 filed on September 28, 2012.
FIELD OF THE INVENTION
The present invention provides an improved process for the preparation of amorphous Levomefolate calcium. The present invention also provides stable amorphous Levomefolate calcium.
BACK GROUND OF THE INVENTION
Levomefolate calcium is dietary supplement, which is therapeutic agent for the treatment of megaloblastic folic acid deficiency anemia, as an antidote for increasing the compatibility of folic acid antagonists, particularly of aminopterin and methotrexate in cancer chemotherapy. Levomefolate calcium is chemically known as N-[4-[[(2-amino-1,4,5,6,7,8-hexahydro-5-methyl-4-oxo-(6S)-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid calcium salt, having the below structure.
Levomefolate and pharmaceutical^ acceptable salts are first disclosed in GB1572137, this patent does not discuss about polymorphic forms. US5124452 and US5223500 disclosed pentahydrate and amorphous forms of Levomefolate calcium.
US 5350850 discloses a process for the preparation of Levomefolate calcium, wherein an aqueous solution of folic acid is hydrogenated with a high stoichiometric excess of sodium borohydride and catalytic amount of ethylenediaminetetraacetic acid (EDTA), treating with formaldehyde, followed by sodium borohydride to obtain Levomefolate calcium.
US 5457202 discloses a process for the resolution of (6R, S)-5-methyltetrahydrofolic acid comprising, N-ethyl-2-aminomethylpyrrolidine were added to (6R, S)-5-methyltetrahydrofolic acid in water. The reaction mixture was heated to dissolve 6S-acid isomer; the undissolved 6R-acid is filtered. The filtrate was cooled to 20°C to precipitate 6S-acid isomer and the crystals were filtered

I f
to obtain N-ethyl-2-aminomethylpyrrolidine salt of (6S)-5-methyltetrahydrofolic acid. The suspension of the above salt is taken in water; calcium chloride is added to form Levomefolate calcium. However, the yields are poor for this reaction due to repeated crystallization.
US 6441168 discloses four crystalline modifications of Levomefolate calcium namely Type-I, Type-ll, Type-Ill and Type-IV. This patent also discloses amorphous Levomefolate calcium, wherein Levomefolate is treated with calcium chloride in water, the obtained solid is filtered at room temperature and dried under vacuum at 45°C to get amorphous product.
WO 2008144953A1 publication, discloses a process for the preparation of amorphous Levomefolate calcium, wherein Levomefolate calcium is crystallized from aqueous ethanol to obtain amorphous Levomefolate calcium.
Accordingly, the present invention relates to a process for the preparation of amorphous Levomefolate calcium, wherein Levomefolate calcium is dissolved in an aqueous medium, the resulting solution is subjected to distillation, crystallization, lyophilization, spray drying or agitated thin film drier (ATFD) to get amorphous Levomefolate calcium.
The present invention also provides an improved process for the preparation of stable amorphous Levomefolate calcium, which obviates the drawback associated in the prior arts.
SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide an improved process for the preparation of stable amorphous Levomefolate calcium.
One aspect of the present invention is to provide an improved process for the preparation of amorphous Levomefolate calcium comprising the steps of;
a) taking chiral base salt of Levomefolate in water,
b) adding calcium chloride,
c) adding anti solvent, and
d) isolating amorphous Levomefolate calcium.
Another aspect of the present invention is to provide an improved process for the preparation of amorphous Levomefolate calcium comprising the steps of;
a) taking Levomefolate calcium in water,
b) heating to get clear solution,

t r
c) optionally adding antioxidant,
d) adding anti solvent,
e) cooling the resulting solution, and
f) filtering to get amorphous Levomefolate calcium.
Yet another aspect of the present invention to provide an improved process for the preparation of mefolate calcium comprising the steps of;
a) dissolving folic acid in aqueous base,
b) adding reducing agent,
c) optionally adding an antioxidant,
d) adding formaldehyde, followed by reducing agent in aqueous base,
e) treating with aqueous calcium chloride solution,
f) filtering the obtained solid, and
g) optionally purifying to get mefolate calcium.
Yet another aspect of the present invention is to provide a process for the preparation of amorphous Levomefolate calcium comprising the steps of;
a) dissolving Levomefolate calcium in water at 40-50°C,
b) adding alcohol solvent at same temperature,
c) raising the temperature to 60-65°C for 1-2hrs,
d) cooling the temperature of step c) to 20-30°C, and
e) filtering pure amorphous Levomefolate calcium.
Yet another aspect of the present invention is to provide stable amorphous Levomefolate calcium comprising;
a) amorphous Levomefolate calcium is packaged in a first closed container that is non-permeable to moisture,
b) the first container is disposed within a second closed container that is non-permeable to moisture,
c) optionally the second container is disposed within a third closed container that is non-permeable to moisture, and
d) space between any two containers is provided with at least one of an inert gas, a desiccant, and an oxygen absorber.
According to the present invention the amorphous Levomefolate calcium schematically shown as below

Yet another aspect of the present invention is to provide a pharmaceutical composition comprising amorphous Levomefolate calcium and pharmaceutical^ acceptable carrier.

BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a representative X-ray diffraction pattern of amorphous Levomefolate calcium. DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a process for the preparation of Levomefolate calcium and a method of packaging thereof. According to the present invention the process for the preparation of amorphous Levomefolate calcium comprises; dissolving Levomefolate calcium in a solvent, followed by removing the solvent by known techniques to get amorphous Levomefolate calcium.
One embodiment of the present invention is to provide an improved process for the preparation of amorphous Levomefolate calcium comprising the steps of;
a) taking chiral base salt of Levomefolate in water,
b) adding calcium chloride,
c) adding anti solvent, and
d) isolating amorphous Levomefolate calcium.
According to the present invention chiral base salt of Levomefolate is suspended in water and calcium chloride is added at room temperature. The mixture is heated to get clear solution; anti-solvent is added, followed by cooling to get precipitation. The obtained compound is filtered to get amorphous Levomefolate calcium.
According to the present invention the chiral base is selected from S-2-amino methyl ethyl pyrrolidine, (S)-l-phenylethylamine, (R)-N-methyM-phenylethylamine or (S) -1-(4-nitrophenyl) ethylamine.
Another embodiment of the present invention is to provide a process for the preparation of amorphous Levomefolate calcium comprising the steps of;
a) taking Levomefolate calcium in water,
b) heating to get clear solution,
c) optionally adding an antioxidant,
d) adding anti-solvent,
e) cooling the resulting solution, and
f) filtering to get amorphous Levomefolate calcium
According to the present invention, Levomefolate calcium is dissolved in water at 35-50°C, the solution is optionally treated with an antioxidant at same temperature, followed by slow addition of

anti-solvent, cooled to room temperature and solvent is removed by filtration or decantation. The obtained amorphous levomefolate calcium is further dried under vacuum at 40-45°C.
According to the present invention, antioxidant is selected from L-ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, sodium ascorbate, citric acid, ct-tocopherol, [3-tocopherol, 6-tocopherol or vitamin E.
According to the present invention, the anti-solvent is selected from methanol, ethanol, propanol, isopropanol or butanol.
Yet another embodiment of the present invention is to provide a process for the preparation of mefolate calcium comprising the steps of:
a) dissolving folic acid in aqueous base,
b) adding reducing agent,
c) optionally adding an antioxidant,
d) adding formaldehyde, followed by reducing agent in aqueous base,
e) treating with aqueous calcium chloride solution,
f) filtering the obtained solid, and
g) optionally purifying to get mefolate calcium.
According to the present invention folic acid is dissolved in aqueous base, reducing agent and antioxidant is added, the reaction mixture is heated to 90-100°C to get clear solution and then cooled to 0-10°C. The pH of the solution is adjusted to 7- 9 with aqueous HCI, followed by addition of formaldehyde and reducing agent in aqueous base medium. The reaction mass is heated to 60-70°C and then cooled to 0-10°C, the pH is adjusted to 6 - 7 to form mefolate, followed by treatment with aqueous calcium chloride to get crude mefolate calcium. The crude mefolate calcium is suspended in water, heated to 90-100°C to get clear solution and then cooled to 5-10°C; the obtained product is filtered and dried under vacuum and unloaded the material in controlled relative humidity (RH) below 50%.
According to the present invention the aqueous base is selected from aqueous sodium hydroxide, aqueous sodium carbonate or aqueous potassium hydroxide; reducing agent is selected from sodium borohydride or sodium cyanoborohydride.
Another embodiment of the present invention is to provide a process for the preparation of amorphous Levomefolate calcium comprising the steps of; a) dissolving Levomefolate calcium in water at 40-50°C,

b) adding alcohol solvent at same temperature,
c) raising the temperature to 60-65°C for 1-2hrs,
d) cooling the temperature of step c) to 20-30°C, and
e) filtering pure amorphous Levomefolate calcium.
According to the present invention Levomefolate calcium is dissolved in water at 40-50°C, added alcoholic solvent selected from methanol, ethanol or isopropanol at same temperature. Reaction mixture temperature is raised to 60-65°C and maintained for about 1-2hrs to get the precipitation. The suspension is slowly cooled to 20-30°C and the obtained solid is filtered, washed with methanol: water (1:1) ratio and dried to get pure amorphous levomefolate calcium.
According to the present invention Levomefolate calcium is dissolved in a solvent. The solvent is selected from water, alcohol solvent, ketone solvent, or mixture thereof, preferably water or aqueous alcohol.
According to the present invention, alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, butanol or pentanol; ketone solvent is selected from acetone, methylethylketone or methylisobutylketone.
According to the present invention Levomefolate is dissolved in a solvent to get clear solution at ambient temperature, the obtained solution is optionally treated with carbon; remove the undissloved particles and carbon by filtration to get clear solution.
According to the present invention spray drying is carried out at 40 °C to 100 °C, preferably at 100°C at 2.0Kg/cm2 nitrogen pressure at a rate of about 2-6ml/min. The obtained product is dried under vacuum at 30-40°C. Lyophilization is carried out for 14 hrs to 24hrs, preferably for 17 hrs.
Yet another embodiment, the particle size distribution of Levomefolate calcium is expressed by Dgo < 250 urn, in certain instances a desired particle size distribution is D90 < 200 urn. Such particle size information can be obtained using a Malvern laser light scattering particle size analyzer and the process is carried out in controlled RH below 50%.
According to the present embodiment, the desired micronized particle size of Levomefolate calcium is expressed by D90 < 50 pm. In certain instances a desired particle size distribution is D90 < 30 urn. Many techniques are useful for particle size reduction, including jet milling. In an embodiment, the material is micronized in a jet mill using gases such as air or nitrogen at pressures about 4.5 to 6 kg/cm2. After completions unload the material under nitrogen

atmosphere and pack the material as per packing condition and the process is carried out in controlled RH below 50%.
Yet another embodiment of the present invention is to provide stable amorphous Levomefolate calcium comprising;
a) amorphous Levomefolate calcium is packaged in a first closed container that is non-permeable to moisture,
b) the first container is disposed within a second closed container that is non-permeable to moisture,
c) optionally the second container is disposed within a third closed container that is non-permeable to moisture,
d) space between any two containers is provided with at least one of an inert gas, a desiccant, and an oxygen absorber, and
e) the process is carried out in controlled RH below 50%
According to the present embodiment, storage-stable amorphous levomefolate calcium is achieved by the procedure of placing amorphous levomefolate calcium into a non-permeable container such as a high molecular low density polyethylene bag (HMLDPE) with or without an inert gas, followed by placing the container into a second non-permeable container such as a triple laminated-aluminum foil bag optionally containing a desiccant pouch, with or without an oxygen absorbent, an inert gas, or both, then further placing the second container into a third non-permeable container such as a triple laminated-aluminum foil bag containing a desiccant pouch and purged with an inert gas, then finally placing the triple laminated bag into a high density polyethylene storage container (Fiber drum or HDPE) and sealing the container. Typically, the bags will each be sealed, such as using a tie or adhesive, heat welding, etc.
According to the present invention, wherein the package is made up of material selected from high molecular low density polyethylene (HMLDPE), Polyethylene (PE), bi-axially oriented polypropylene (BOPP) or PET (polyethylene terephthalate) or oriented polyamide (OPA) or aluminum foil, or a blend thereof or a laminated structure of these polymers.
According to the prior art, the amorphous levomefolate calcium is unstable and leads to formation of crystallinity and impurities due to improper storage conditions. The present invention provides stable amorphous form with the above packaging conditions.
Yet another embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous Levomefolate calcium and pharmaceutically acceptable carrier.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.
EXPERIMENTAL SECTION
Powder X-ray Diffraction (PXRD)
The X-ray diffraction patterns of said polymorphs of the invention were measured on Bruker D8 Discover powder diffractometer equipped with goniometer of q/q configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 28 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
Example: 1
Preparation of mefolate calcium.
Sodium hydroxide (28g) was dissolved in water (1000ml) at room temperature under nitrogen atmosphere, folic acid(100g), L-ascorbic acid (5g) were added, cooled to 10-30°C and sodium borohydride solution [Sodium borohydride(86g) was dissolved in 1% sodium hydroxide solution(300ml)] was added. The reaction mass was heated to 90-100°C, maintained for 1-2 hours and then cooled to 0-10°C; pH was adjusted to 7 - 9 with aqueous hydrochloric acid and then added formaldehyde(48g, 37%), followed by sodium borohydride solution[Sodium borohydride(34g)was dissolved in 1% sodium hydroxide solution(200ml)] at 0-10°C. The reaction mass was heated to 60-70°C, maintained for 1hour, cooled to 0-10°C and adjusted pH 6-8 with aqueous hydrochloric acid. The obtained salts were filtered and washed with water (400ml). The filtrate was cooled to 0-10° C; calcium chloride solution [calcium chloride (67g) was dissolved in water (100ml)] was added and stirred for overnight. The obtained crude compound was filtered and washed with water (500ml). The crude compound was dissolved in water (1500ml) at 80-100°C, cooled to 0-10°C and stirred for 2-4 hours. The obtain product was filtered and washed with water (200ml), dried under vacuum at 35-50°C to get a mefolate calcium; If HPLC purity is not complies, then repeat the last water purification step to get the title compound. This process is carried out in controlled relative humidity (RH) below 50%. Weight: 90g.
Example: 2
Preparation of Levomefolate (S)-2-aminomethyl-1 -ethyl pyrrolidine salt.
Levomefolate calcium (100g) was taken in water (500ml) and ethylenediaminetetraacetic acid (50g) was added, followed by S-2-amino methyl ethyl pyrrolidine (45g) at room temperature under nitrogen atmosphere. The reaction mass was heated to 80-90°C, maintained for 1-2 hrs, then

cooled to 60 -70°C and R-isomer was separated by filtration. The filtrate was cooled to 0-20° C, stirred for 4-6 hours, filtered and washed with water (100ml) to get crude product. The crude product was taken in water (200ml), heated to 70-80°C to get clear solution and cooled to 40-50°C. The obtain material was filter and washed with water (100ml), further dried under vacuum at 40-50°C to obtain Levomefolate (S)-2-aminomethyl-1 -ethyl pyrrolidine salt ; If HPLC purity is not complies, then repeat the last water purification step to get the title compound. This process is carried out in controlled relative humidity (RH) below 50%. Weight: 40 g.
Example: 3
Preparation of Levomefolate calcium
Levomefolate (S)-2-aminomethyl-1-ethyl pyrrolidine salt (100g) was dissolved in water (600ml), followed by calcium chloride dihydrate (50gm).The reaction mixture was stirred at 45°C and treated with active carbon BW-280. The reaction mass is cooled to 10-20°C and stirred for 5 to 10 hrs at same temperature. The obtain precipitate was filtered and dried under vacuum in presence of nitrogen to get crude Levomefolate calcium. The obtained crude Levomefolate calcium (70 g) was taken in water (600ml) and 50% aqueous sodium hydroxide (30ml) was added at room temperature under nitrogen atmosphere. The reaction mass was stirred at 30 to 35°C and adjusted pH 5-8 with aqueous hydrochloride solution at same temperature; followed by calcium chloride solution (42gm in 70ml of water). The resultant precipitate was stirred, filtered and dried under vacuum in presence of nitrogen atmosphere to get Levomefolate calcium. Weight: 40 g
Example: 4
Preparation of amorphous Levomefolate calcium
Method-a:
Levomefolate calcium (100g) was dissolved in water (1000ml) at 40-50°C. Methanol (2000ml)
was slowly added to the solution at 40-50°C, the temperature was raised to reflux and cooled to room temperature. The solid was filtered and dried at 40-45°C under vacuum to obtain amorphous form of Levomefolate calcium. If HPLC purity is not complies, then repeat the same process to get the purity of title compound. Weight: 80 g
Method-b:
Levomefolate calcium (5g) was dissolved in water (50ml) at 20-60°C, sodium ascorbate (0.1g)
was added. Methanol (100ml) was slowly added to the solution at 20-60°C, the temperature was raised to reflux and cooled to room temperature. The solid was filtered and dried at 20-60°C

under vacuum to obtain amorphous form of Levomefolate calcium and the process is carried out in controlled RH below 60%. Weight: 3.5g
Method-c:
Levomefolate calcium (5g) was dissolved in water (50ml) at 40-50°C. Ethanol (100ml) was slowly
added to the solution at 40-50°C, the temperature was raised to reflux and cooled to room temperature. The solid was filtered and dried at 40-45°C under vacuum to obtain amorphous form of Levomefolate calcium. Weight: 3.5g
Method-d:
Levomefolate (S)-2-Aminomethyl-1-ethyl pyrrolidine (5g) was taken in water (30ml), calcium
chloride (2.5g) was added at room temperature under nitrogen atmosphere. The mixture was heated to 35-40°C to get clear solution. Ethanol (60ml) was slowly added to a reaction mass at 35-40°C and cooled to 20-25°C. The solid was filtered and dried at 40-45°C under vacuum to obtain amorphous form of Levomefolate calcium. Weight: 4.0g
Method-e:
Levomefolate calcium (5g) was dissolved in water (50ml) at 40-50°C. This solution was added to
ethanol (100ml) at same temperature and then cooled to room temperature. The solid was filtered and dried at 40-45°C under vacuum to obtain amorphous form of Levomefolate calcium. Weight: 3.5g
Example 5
Preparation of amorphous Levomefolate calcium.
Levomefolate calcium (1g) was dissolved in water (80ml) at room temperature and the solution was filtered. The clear solution was freeze and lyophilized for 17 hrs. The solid obtained was identified as amorphous Levomefolate calcium. Weight: 0.85gm
Example 6
Preparation of amorphous Levomefolate calcium.
Levomefolate calcium (4g) was dissolved in water (320ml) at room temperature and the solution was filtered. The clear solution was spray dried at about 100°C 2.0 kg/cm2 nitrogen pressure, aspirator at 100% and at rate of about 4ml per minute. The material was recovered from receiver

and further dried under vacuum at 30-40°C. The solid obtained was identified as amorphous Levomefolate calcium. Weight: 0.75gm
Example 7
Preparation of amorphous Levomefolate calcium.
Levomefolate pyrrolidine salt (1g) was suspended in water (6ml) and then added calcium chloride (0.42g) at room temperature under nitrogen atmosphere. The solution was heated to 35-40°C and treated with activated carbon (0.05g).The aqueous solution was washed with dichloromethane (5ml x 2). The aqueous solution was freeze and lyophilized for 17 hrs. The solid obtained was identified as amorphous Levomefolate calcium. Weight: 0.80gm
Example: 8
Packing conditions for stable amorphous Levomefolate calcium
Amorphous Levomefolate calcium was packed under different packing conditions. The process is carried out in controlled RH below 60%
Packaging condition 1
Amorphous Levomefolate calcium was placed in innermost HMLDPE bag twisted, tied and kept in middle triple laminated aluminum liner with one o-buster and one silica gel, which was heat sealed under vacuumised nitrogen. Finally placed it in outer triple laminated aluminum bag, which was heat sealed under vacuumised nitrogen and kept in fiber drum.
Packaging condition 2
Amorphous Levomefolate calcium was placed in innermost triple laminated aluminum liner, which was heat sealed under vacuumised nitrogen and kept in middle triple laminated aluminum liner with one o-buster and one silica gel, which was heat sealed under vacuumised nitrogen. Finally placed it in outer triple laminated aluminum bag, which was heat sealed under vacuumised nitrogen and kept in fiber drum.
Packing Condition 3
Amorphous Levomefolate calcium was placed in glass bottle, heat sealed and kept in middle triple laminated aluminum liner with one o-buster and one silica gel, which was heat sealed under

vacuumised nitrogen. Finally placed it in outer triple laminated aluminum bag, which was heat sealed under vacuumised nitrogen.
Packing Condition 4
Amorphous Levomefolate calcium was placed in glass bottle, which was heat sealed/aluminum sealed and kept in middle triple laminated aluminum liner with one o-buster and one silica gel, which was heat sealed under vacuumised nitrogen.
Packing Condition 5
Amorphous Levomefolate calcium was placed in aluminium, heat sealed and kept in middle triple laminated aluminum liner with one o-buster and one silica gel, which was heat sealed under vacuumised nitrogen. Finally placed it in outer triple laminated aluminum bag, which was heat sealed under vacuumised nitrogen.
Packing Condition 6
Amorphous Levomefolate calcium was placed in aluminium, heat sealed/aluminum sealed and kept in middle triple laminated aluminum liner with one o-buster and one silica gel, which was heat sealed under vacuumised nitrogen.
Procedure for micronization:
Inserted new bag was placed in clean micronizer under nitrogen pressure 4-6 kg/cm2. The sample was subjected to micronization in air jet mill to produce a solid material having desired particle size distribution, after completion of the micronization; the material was packed as per packing condition.
PSD DATA

WE CLAIM:
1. An improved process for the preparation of amorphous Levomefolate calcium comprising
the steps of;
a) taking chiral base salt of Levomefolate in water,
b) adding calcium chloride,
c) adding anti solvent, and
d) isolating amorphous Levomefolate calcium.

2. The process according to claim 1, wherein the chiral base is selected from S-2-amino methyl ethyl pyrrolidine, (S)-l-phenylethylamine, (R)-N-methyl-l-phenylethylamine or (S) -1-(4-nitrophenyl) ethylamine.
3. The process according to claim 1, wherein isolation is carried out by known techniques like filtration, distillation, lyophilization, spray drying and agitated thin film dryer to get amorphous Levomefolate calcium.
4. Process for the preparation of pure amorphous Levomefolate calcium, comprising the steps of;

a) dissolving Levomefolate calcium in water at 40-50°C,
b) adding alcohol solvent at same temperature,
c) raising the temperature to 60-65°C for 1-2hrs,
d) cooling the temperature of step c) to 20-30°C, and
e) filtering pure amorphous Levomefolate calcium.
5. An improved process for the preparation of amorphous Levomefolate calcium comprising
the steps of;
a) taking Levomefolate calcium in water,
b) heating to get clear solution,
c) optionally adding an antioxidant,
d) adding anti-solvent,
e) cooling the resulting solution, and
f) filtering to get amorphous Levomefolate calcium.
6. The process according to claims 1 and 5, wherein the anti-solvent is selected from
methanol, ethanol, propanol, isopropanol or butanol.

7. An improved process for the preparation of mefolate calcium comprising the steps of:
a) dissolving folic acid in aqueous base,
b) adding reducing agent,
c) optionally adding an antioxidant,
d) adding formaldehyde, followed by reducing agent in aqueous base,
e) treating with aqueous calcium chloride solution,
0 filtering the obtained solid, and
g) optionally purifying to get mefolate calcium.
8. The process according to claim 7, wherein the aqueous base is selected from aqueous sodium hydroxide, aqueous sodium carbonate or aqueous potassium hydroxide; reducing agent is selected from sodium borohydride or sodium cyanoborohydride
9. The process according to claims 5 and 7, wherein the antioxidant is selected from L-ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, sodium ascorbate, citric acid, a-tocopherol, (3-tocopherol, 5-tocopherol or vitamin E;
10. Stable amorphous Levomefolate calcium comprising;

a) amorphous Levomefolate calcium is packaged in a first closed container that is non-permeable to moisture,
b) the first container is disposed within a second closed container that is non-permeable to moisture,
c) optionally the second container is disposed within a third closed container that is non-permeable to moisture,
d) space between any two containers is provided with at least one of an inert gas, a desiccant, and an oxygen absorber, and
e) the process is carried out in controlled RH below 50%.